US-12624397-B2 - Biomarkers associated with anti-IL-36R antibody treatment in generalized pustular psoriasis

US12624397B2US 12624397 B2US12624397 B2US 12624397B2US-12624397-B2

Abstract

This invention generally relates to biomarkers associated with anti-IL-36R antibody treatment in generalized pustular psoriasis (GPP). The invention also relates to methods of using the biomarkers disclosed.

Inventors

Patrick BAUM
Ahmed Karim FARAG
Sudha Visvanathan

Assignees

BOEHRINGER INGELHEIM INTERNATIONAL GMBH

Dates

Publication Date: 20260512
Application Date: 20220310

Claims (2)

1 . A method of monitoring a GPP patient's beneficial response and adjusting treatment for generalized pustular psoriasis (GPP) in a GPP patient experiencing an acute flare after administration of a single intravenous dose of an anti-interleukin-36 receptor antibody (anti-IL-36R antibody), comprising: a) obtaining, at baseline (pre-dose) and at weeks 1, 2 and/or 4 post-administration blood form the GPP patient; b) isolating plasma and quantifying in each time-point sample the expression level or concentration of at least three GPP biomarkers selected from pro-inflammatory processes (TNF, IL1B, IL6), neutrophil recruitment (CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL8, CXCR1, CXCR1, CXCR2), neutrophil occurrence (NCF1, NCF2, NCF4, ELANE) or in keratinocyte activation, differentiation and mediated inflammation transcripts (IL36A, IL36G, IL17C, IL19, IL20, IL22, IL24), CSF3, IL24, IL19, IL20, IL6, IL17C, IL12B, RN7SL471P, PTX3, MRGPRX3, LBP, CAMP, IL23A, RND1, ADAMTS4, SPOCD1, MRPL12, CXCL1, GOS2, SPATA20P1, SH2D5, SOCS3, PHLDA2, MGAM, SLC26A4, MMP9, PADI4, FOSL1, PDCD1, MT2A, SPRR2C, P2RY6, C2CD4A, OSM, IL1B, CYP27B1, PRSS22, FCGBP, LILRA5, SERPINA3, SNAI1, TGM2, CNGB1, MAMDC4, MT1G, JUNB, SOCS1 or CASP5 by a validated QPCR assay, ELISA, or other protein detection method c) computing, with a configured processor executing a pre-specified analysis pipeline, an activation z-score using pathway analysis at each post-dose time-point, the score comprising biomarker measurements relative to baseline; (d) classifying the patient as a responder when said biomarker score indicates ≥50% down-regulation relative to baseline at post-dose time-points; and (e) optionally adjusting treatment for the patient based on the classification, comprising administering an additional anti-IL-36R dose within 1-4 weeks.
2 . The method of claim 1 , wherein the anti-IL-36R antibody is spesolimab.

Description

SEQUENCE LISTING The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Feb. 17, 2022 is named 09-0718-US-3-2022-03-10-SL.txt and is 146,122 bytes in size. TECHNICAL FIELD OF THE INVENTION This invention generally relates to biomarkers associated with anti-IL-36R antibody treatment in generalized pustular psoriasis (GPP). More specifically, the invention relates to biomarkers associated with spesolimab treatment in GPP. The invention also relates to methods of using the biomarkers disclosed herein. BACKGROUND OF THE INVENTION Pustular psoriasis comprises a spectrum of severe chronic or relapsing inflammatory skin conditions with recurrent or persistent eruptions of painful neutrophilic sterile pustules. Patients with pustular psoriasis can present with different clinical phenotypes and a predominant recognised subtype is generalized pustular psoriasis (GPP). GPP is a rare disease characterised by episodes of widespread eruption of macroscopically visible pustules and may be accompanied by systemic inflammation. It is associated with significant morbidity and can be life-threatening without appropriate treatment. Several studies in GPP have reported overexpression of interleukin-36 (IL-36) in skin lesions and loss-of-function mutations in the gene encoding for the IL-36 receptor (IL-36R) antagonist (IL36RN), as well as mutations in other genes with functional connection with the IL-36 pathway, among others, namely CARD14, APS1S3 and SERPINA3. IL36RN mutations alter the normal function of the IL-36 receptor antagonist, leading to reduced inhibition of the IL-36R pathway due to an imbalanced competitive binding against IL-36a, IL-36P and IL-36γ. This in turn leads to induction of the downstream inflammatory cascade and recruitment of neutrophils, in addition to other innate and adaptive immune cells. IL36RN mutations have been reported in 10-82% of patients with GPP, and an earlier age of onset has been described in patients with GPP who have defective IL36RN mutations. Furthermore, a study investigating the impact of different IL36RN mutations on IL-36Ra protein expression and regulatory function showed that null mutants tend to be preferentially associated with GPP, whereas hypomorphic mutations were found in GPP. The key role of the IL-36 axis in GPP is further supported by studies demonstrating significant contributions for IL-17A, IL-23, tumour necrosis factor (TNF), IL-1, IL-36 and type 1 interferon in the pathogenesis of GPP lesions. Among the upregulated genes, predominance of IL-1- and IL-36-related transcripts was reported. In addition, strong expression of IL-36a and IL-36γ in keratinocytes proximal to neutrophilic pustules have also been detected in GPP lesions. Overall, there is sufficient evidence to suggest that the blockade of IL-36R signalling is an appealing targeted therapeutic approach for patients with GPP. Previously, blockade of IL-36R signalling with a single intravenous dose of 10 mg/kg spesolimab, a novel humanised anti-IL-36R monoclonal antibody, in a proof-of-concept Phase I, multicentre, single-arm, open-label study (ClinicalTrials.gov identifier: NCT02978690) showed rapid skin and pustular clearance in patients presenting with an acute GPP flare. However, the inflammatory circuits and cellular interactions driving the pathogenesis of GPP are not yet fully elucidated, and the mechanisms by which these are disrupted by IL-36R blockade are unknown. There is therefore a need for improved means to follow the efficacy of treatment options against GPP, identify patients that will most benefit from these treatments in GPP, and to determine and adjust the dosages of therapies for patients as may be needed. SUMMARY OF THE INVENTION The present invention addresses the above needs and provides biomarkers associated with anti-IL-36R antibody treatment in generalized pustular psoriasis (GPP). In one embodiment, the present invention provides a method for detecting the presence or absence of a beneficial response in a patient after administration of an anti-interleukin 36 receptor antibody (anti-IL-36R antibody) (e.g., spesolimab), comprising: a) obtaining a biological sample from the patient; b) measuring in said sample the level of expression of one or more biomarkers; c) comparing the level to control value of the level of the biomarkers; and d) determining whether or not the difference in levels between the sample and the control reflects a beneficial response in the patient, wherein the one or more biomarkers comprise genes/proteins associated with the pro-inflammatory mediators (TNF, IL1B, IL6), neutrophil recruitment mediators (CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL8, CXCR1, CXCR1, CXCR2), neutrophil-expressed transcripts (NCF1, NCF2, NCF4, ELANE) or in keratinocyte activation, differentiation and mediated inflammation transcripts (IL36A, IL36G, IL17C,